438 Antidiabetics acute heart failure, recent myocardial infarction, or firmed, although one suggests that no special precaution is need- Profile ed for patients with normal serum-creatinine who are to be given Buformin is a biguanide antidiabetic (p.437). It has been given shock, may increase the risk of lactic acidosis. Other 3 conditions that may also predispose to lactic acidosis in a low volume of iodinated contrast medium (up to 100 mL). orally in the treatment of type 2 diabetes mellitus (p.431) in doses 1. Committee on Drugs and Contrast Media, Commission on Gen- of up to 300 mg daily. Buformin is also used as the hydrochlo- a patient taking a biguanide include excessive alcohol eral and Pediatric Radiology of the American College of Radiol- ride. intake and hepatic impairment. Biguanides should be ogy. Manual on contrast media, 5th ed. Available at: http:// www.acr.org/SecondaryMainMenuCategories/quality_safety/ Preparations temporarily stopped for examinations using contrast contrast_manual.aspx (accessed 26/06/07) Proprietary Preparations (details are given in Part 3) media (see under Interactions, below). 2. Benko A, et al. Canadian Association of Radiologists: consensus Cz.: Adebit†; Silubin†; Hung.: Adebit; Spain: Silubin†; Switz.: Silubin†. guidelines for the prevention of contrast-induced nephropathy. Insulin is preferred for the treatment of diabetes in Can Assoc Radiol J 2007; 58: 79–87. Correction available at: http://www.car.ca/Files%5CNephropathy.pdf (accessed pregnancy. 20/08/08) [correct version] Carbutamide (BAN, rINN) Owing to the possibility of decreased vitamin B ab- 3. Board of the Faculty of Clinical Radiology; The Royal College 12 of Radiologists. Standards for iodinated intravascular contrast BZ-55; Ca-1022; Carbutamida; Carbutamidum; Glybutamide; sorption, annual monitoring of vitamin B12 concentra- agent administration to adult patients (issued November 2005). Karbutamid; Karbutamidi; U-6987. 1-Butyl-3-sulphanilylurea. tions is advisable during long-term treatment. Available at: http://www.rcr.ac.uk/docs/radiology/pdf/ IVcontrastPrintFinal.pdf (accessed 26/06/07) Карбутамид 4. European Society of Urogenital Radiology. ESUR guidelines on Driving. In the UK, patients with diabetes mellitus treated with C11H17N3O3S = 271.3. contrast media (version 6.0, issued February 2007). Available at: CAS — 339-43-5. insulin or oral hypoglycaemics are required to notify their condi- http://www.esur.org/fileadmin/Guidelines/ESUR_2007_ tion to the Driver and Vehicle Licensing Agency, who then assess Guideline_6_Kern_Ubersicht.pdf (accessed 26/06/07) ATC — A10BB06. their fitness to drive. Patients treated with oral hypoglycaemics ATC Vet — QA10BB06. Platelet counts in 10 diabetic patients receiving are generally allowed to retain standard driving licences; those Ketotifen. biguanides fell (markedly in 3 patients) when they were also giv- treated with insulin receive restricted licences which must be re- en ketotifen.1 Counts returned to normal a few days after the end newed (with appropriate checks) every 1 to 3 years. Patients O O O of ketotifen therapy. However, the investigators did not consider should be warned of the dangers of hypoglycaemic attacks while the effect clinically significant. driving, and should be counselled in appropriate management of S 1. Doleček R. Ketotifen in the treatment of diabetics with various N N CH3 the situation (stopping driving as soon as it is safe to do so, taking allergic conditions. Pharmatherapeutica 1981; 2: 568–74. H H carbohydrate immediately, and quitting the driving seat and re- Sulfonylureas. For reference to an apparent increase in mortal- moving the ignition key from the car) should such an event oc- H2N cur. Patients who have lost hypoglycaemic awareness, or have ity with an intensive regimen of metformin plus a sulfonylurea, frequent hypoglycaemic episodes, should not drive. In addition, see p.462. Profile eyesight must be adequate (field of vision of at least 120°) for a Carbutamide is a sulfonylurea antidiabetic (p.460). It is given licence to be valid. Patients treated with diet or oral hypoglycae- Uses and Administration orally in the treatment of type 2 diabetes mellitus (p.431) in sin- mics are normally allowed to hold vocational driving licences for The biguanide antidiabetics are a class of oral antidia- gle daily doses of 0.5 to 1 g, but is more toxic than chlorpropa- heavy goods vehicles or passenger carrying vehicles; those treat- betic drugs used in the treatment of type 2 diabetes mide. ed with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses. mellitus (p.431). They are given to supplement treat- Preparations ment by diet modification when such modification has References. Proprietary Preparations (details are given in Part 3) not proved effective on its own. In addition, because Fr.: Glucidoral. 1. British Diabetic Association (Diabetes UK). Information sheet: driving and diabetes: May 2008. Available at: biguanides are not associated with weight gain they are http://www.diabetes.org.uk/Documents/catalogue/driving_and_ preferred in obese patients. Although sulfonylureas diabetes-may_08.pdf (accessed 20/08/08) (p.460) may be preferred in non-obese patients, a Chlorpropamide (BAN, rINN) 2. Driver and Vehicle Licensing Agency. For medical practitioners: biguanide is often added or given instead to patients at a glance guide to the current medical standards of fitness to Chloropropamid; Chlorpropamid; Chlorpropamidas; Chlo- drive (February 2008). Available at: http://www.dvla.gov.uk/ who are not responding to a sulfonylurea. media/pdf/medical/aagv1.pdf (accessed 14/08/08) rpropamidum; Clorpropamida; Klooripropamidi; Klórpropamid; The mode of action of biguanides is not clear. They do Klorpropamid. 1-(4-Chlorobenzenesulphonyl)-3-propylurea. Interactions not stimulate insulin release but require that some insu- Хлорпропамид lin be present in order to exert their antidiabetic effect. Use of a biguanide with other drugs that lower blood- C10H13ClN2O3S = 276.7. Possible mechanisms of action include delay in the ab- glucose concentrations increases the risk of hypogly- CAS — 94-20-2. sorption of glucose from the gastrointestinal tract, an ATC — A10BB02. caemia, while drugs that increase blood glucose may increase in insulin sensitivity and glucose uptake into ATC Vet — QA10BB02. reduce the effect of biguanide therapy. cells, and inhibition of hepatic gluconeogenesis. In general fewer drug interactions have been reported Biguanides do not usually lower blood-glucose con- O O with biguanides than with sulfonylureas. Alcohol may centrations in non-diabetic subjects. O increase the risk of lactic acidosis as well as of hy- S Hyperlipidaemias. The effect of biguanides on lipid metabo- CH3 poglycaemia. Care should be taken if biguanides are lism is unclear, although some studies have shown a beneficial N N given with drugs that may impair renal function. effect on serum-lipid profiles in both obese and lean patients with H H type 2 diabetes, hypertension, and/or hyperlipidaemia.1 Reduc- Cl Anticoagulants. For the effect of metformin on phenprocou- tions in concentrations of total cholesterol, low-density and very mon activity, see Antidiabetics, p.1428. low-density-lipoprotein cholesterol have been reported, as well Pharmacopoeias. In Chin., Eur. (see p.vii), Jpn, and US. 1 as modest increases in high-density-lipoprotein cholesterol. Antivirals. Fatal lactic acidosis has been reported in a patient Ph. Eur. 6.2 (Chlorpropamide). A white or almost white, crys- Some studies have also reported a reduction in serum-triglycer- given metformin with didanosine, stavudine, and tenofovir. talline powder. It exhibits polymorphism. Practically insoluble in ide levels. Such effects may be beneficial in the long-term treat- water; soluble in alcohol; freely soluble in acetone and in dichlo- 1. Worth L, et al. A cautionary tale: fatal lactic acidosis complicat- ment of type 2 diabetes mellitus with concomitant lipid disor- ing nucleoside analogue and metformin therapy. Clin Infect Dis romethane; dissolves in dilute solutions of alkali hydroxides. ders. 2003; 37: 315–16. Protect from light. 1. Dunn CJ, Peters DH. Metformin: a review of its pharmacological Cimetidine. Cimetidine increased plasma-metformin concen- properties and therapeutic use in non-insulin-dependent diabetes USP 31 (Chlorpropamide). A white crystalline powder having trations in 7 healthy subjects.1 The renal clearance of metformin mellitus. Drugs 1995; 49: 721–49. a slight odour. Practically insoluble in water; soluble in alcohol; sparingly soluble in chloroform. was reduced; competition for proximal tubular secretion was Polycystic ovary syndrome. For discussion of the potential of considered responsible. A reduction in metformin dosage may be metformin in polycystic ovary syndrome, see p.454. required in patients taking metformin and cimetidine, in order to Adverse Effects and Treatment reduce the risk of lactic acidosis. Preparations As for sulfonylureas in general, p.460. 1. Somogyi A, et al. Reduction of metformin renal tubular secre- Proprietary Preparations (details are given in Part 3) Chlorpropamide may be more likely than other sulfo- tion by cimetidine in man. Br J Clin Pharmacol 1987; 23: Mex.: Azucaps†. 545–51. Multi-ingredient: Mex.: Glinorboral. nylureas to induce a syndrome of inappropriate secre- tion of antidiuretic hormone characterised by water re- Contrast media. Biguanides should be temporarily stopped for examinations